Calcium hydrogenorthophosphate

Endpoint summary

Description of key information

Skin irritation (similar to OECD 404, RL2): not irritating 
Eye irritation (OECD 405, RL1): not irritating

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

Animals were examined at 24 and 72 hours only. No data reported on reversibility of effects. Study uses intact and abraded skin. No controls were included in the study.

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

Animals were examined at 24 and 72 hours only. No data reported on reversibility of effects. Study uses intact and abraded skin. No controls were included in the study.

GLP compliance:

no

Remarks:

study pre-dates GLP

Species:

rabbit

Strain:

not specified

Details on test animals or test system and environmental conditions:

No data

Type of coverage:

occlusive

Preparation of test site:

other: Shaved, abraded and intact

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied : 0.5 g


VEHICLE
Used as received.

Duration of treatment / exposure:

24 hours

Observation period:

Up to 72 hours

Number of animals:

6, 3 males and 3 females.

Details on study design:

TEST SITE
- Type of wrap if used: Rubber (occlusive)


REMOVAL OF TEST SUBSTANCE
No data


SCORING SYSTEM:
The Draize dermal method of testing primary irritant substance as described in the Code of Federal Refulations under the Federal Hazardous Substances Labelling Act, Part 191.11, Chapter 1, Title 21.

Compounds producing combined averages (primary irritation indexes) of 2 or less are only mildly irritating; indexes from 2 to 5 are moderate irritants and those with scores above 5 are considered severe or primary irritants.

Irritation parameter:

erythema score

Basis:

mean

Remarks:

6 animals

Time point:

other: 24/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

mean

Remarks:

6 animals

Time point:

other: 24/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Other effects:

No data

Table 1: Results for Dicalcium phosphate

Exposure time Hours	Rabbit No.							Mean
		8M	15M	16M	32F	33F	34F
		Score	Score	Score	Score	Score	Score
Erythema
24	Intact	0	0	0	0	0	0	0.0
72	Intact	0	0	0	0	0	0	0.0
24	Abraded	0	0	0	0	0	0	0.0
72	Abraded	0	0	0	0	0	0	0.0
Subtotal								0.0
Oedema
24	Intact	0	0	0	0	0	0	0.0
72	Intact	0	0	0	0	0	0	0.0
24	Abraded	0	0	0	0	0	0	0.0
72	Abraded	0	0	0	0	0	0	0.0
Subtotal								0.0
Total score								0.0
(Total/4) Primary Irritation Index								0.0
Result							Non-Irritant

 

Interpretation of results:

GHS criteria not met

Conclusions:

No effects were noted throughout the study. Dicalcium phosphate is a non-irritant to both intact and abraded skin.
This study has been selected as the key study because the results are sufficient in order to derive a reliable conclusion on classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP). Calcium hydrogenorthophosphate is not considered to be classified according to Regulation (EC) No. 1272/2008 (EU CLP) as no effects for the parameters erythema/eschar or oedema are noted.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

19 January 2011 - 22 January 2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Deviations:

yes

Remarks:

Specific information related to the characterisation of the test substance as received and as tested is the responsibility of the study Sponsor.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

Specific information related to the characterisation of the test substance as received and as tested is the responsibility of the study Sponsor.

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

Specific information related to the characterisation of the test substance as received and as tested is the responsibility of the study Sponsor.

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Robinson Services, Inc. Clemmons, NC
- Age at study initiation: Young adult
- Housing: Animals were singly housed in suspended stainless steel caging with mesh floors, which conform to the size recommendations in the most recent guide for the care and use of laboratory animals (Natl. Res. Council, 1996). Litter paper was placed beneath the cage and was changed at least 3 times a week.
- Diet: ad libitum; Pelleted Purina Rabbit Chow #5326
- Water: ad libitum, filter tap water was dispensed by an automatic dispensing system.
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%):31-45
- Air changes (per hr): 14
- Photoperiod (hrs dark / hrs light): 12 hr light/dark cycle

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 mg

Duration of treatment / exposure:

4 hours

Observation period (in vivo):

1, 24, 48 and 72 hours

Number of animals or in vitro replicates:

3

Details on study design:

The left eye of each rabbit was left untreated and served as a control.

SCORING SYSTEM: Ocular irritation was evaluated using a high intensity white light (Mag Lite) in accordance with Draize et al (1944) at 1, 24, 48 and 72 hours post-installation. A fluorescein dye procedure was used in the treated eye at 24 hours to evaluate the absence of corneal damage.

TOOL USED TO ASSESS SCORE: fluorescein and high-intensity white light.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

mean

Time point:

24/48/72 h

Score:

0.44

Max. score:

3

Reversibility:

fully reversible within: 72 hrs

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

There was no irititis observed in any treated eye during this study. One hour post-instillation, all three rabbits exhibited corneal opacity and ‘positive’ conjunctivitis. The overall incidence and severity of irritation decreased with time. All animals were free of ocular irritation by 72 hours.

Other effects:

Apart from the ocular irritation noted above, the animals appeared active and healthy during the study. There were no signs of acute toxicity, abnormal behaviour or adverse pharmacologic effects.

Table 1. Individual scores for ocular irritation

	Rabbit No. 3401 (F)				Rabbit No. 3402 (F)				Rabbit No. 3403 (F)
Observation time	1h	24h	48h	72h	1h	24h	48h	72h	1h	24h	48h	72h
Cornea
Opacity	1	0^1	0	0	1	0^1	0	0	1	0^1	0	0
Area	2	4	4	4	1	4	4	4	1	4	4	4
Iris	0	0	0	0	0	0	0	0	0	0	0	0
Conjunctivae
Redness	2	1	1	0	2	1	0	0	2	1	0	0
Chemosis	1	0	0	0	1	0	0	0	1	0	0	0
Discharge	2	1	0	0	2	1	0	0	2	1	0	0

¹2% ophthalmic fluorescein sodium used to evaluate the absence of corneal opacity

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study dicalcium phosphate (with 10% monocalcium phosphate) was determined to be not classified in accordance with the Guidance on the application of Regulation (EC) No. 1272/2008 (EU CLP).
This study is considered to be acceptable and reliable for use as a key study and for classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP).

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

13 December 2010 - 16 December 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

This study is conducted according to an appropriate guideline and under the conditions of GLP, the study is therefore considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement for this endpoint. However as a key study is already available (and this data was provided from a source outside of the EU) it is not required as a key study and therefore the Inorganic Phosphates Consortium have not paid for a letter of access to this data but has agreed with the data owner that a summary can be included in the IUCLID.

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Deviations:

yes

Remarks:

No in process inspection was performed due to early termination of the study. Specific information related to the characterisation of the test substance as received and as tested is the responsibility of the study Sponsor.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

No in process inspection was performed due to early termination of the study. Specific information related to the characterisation of the test substance as received and as tested is the responsibility of the study Sponsor.

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

No in process inspection was performed due to early termination of the study. Specific information related to the characterisation of the test substance as received and as tested is the responsibility of the study Sponsor.

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Robinson Services, Inc. Clemmons, NC
- Age at study initiation: Young adult
- Housing: Animals were singly housed in suspended stainless steel caging with mesh floors, which conform to the size recommendations in the most recent guide for the care and use of laboratory animals (Natl. Res. Council, 1996). Litter paper was placed beneath the cage and was changed at least 3 times a week.
- Diet (e.g. ad libitum): ad libitum; Pelleted Purina Rabbit Chow #5326
- Water (e.g. ad libitum): ad libitum, filter tap water was dispensed by an automatic dispensing system.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-22°C
- Humidity (%):21-40%
- Air changes (per hr): 11 or 14
- Photoperiod (hrs dark / hrs light): 12 hr light/dark cycle

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 mg

Duration of treatment / exposure:

4 hours

Observation period (in vivo):

1, 24, 48, and 72 hours

Number of animals or in vitro replicates:

3

Details on study design:

The left eye of each rabbit was left untreated and served as a control.

SCORING SYSTEM: Ocular irritation was evaluated using a high intensity white light (Mag Lite) in accordance with Draize et al (1944) at 1, 24, 48 and 72 hours post-installation. A fluorescein dye procedure was used in the treated eye at 24 hours to evaluate the absence of corneal damage.

TOOL USED TO ASSESS SCORE: fluorescein and high-intensity white light.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

other: mean score following grading at 24, 48 and 72 hrs

Score:

0

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritant / corrosive response data:

There was no corneal opacity or irititis observed in any treated eye during this study. One hour post-instillation, two animals exhibited positive conjunctivitis and one animal exhibited minimal conjunctivitis. The overall incidence and severity of irritation decreased with time. All animals were free of ocular irritation by 24 hours.

Other effects:

Apart from the ocular irritation noted at 1 hour post-instillation, the animals appeared active and healthy during the study. There were no signs of acute toxicity, abnormal behaviour or adverse pharmacologic effects.

Table 1. Individual scores for ocular irritation

	Rabbit No. 3401 (M)				Rabbit No. 3402 (M)				Rabbit No. 3403 (M)
Observation time	1h	24h	48h	72h	1h	24h	48h	72h	1h	24h	48h	72h
Cornea
Opacity	0	0^1	0	0	0	0^1	0	0	0	0^1	0	0
Area	4	4	4	4	4	4	4	4	4	4	4	4
Iris	0	0	0	0	0	0	0	0	0	0	0	0
Conjunctivae
Redness	2	0	0	0	1	0	0	0	2	0	0	0
Chemosis	1	0	0	0	0	0	0	0	1	0	0	0
Discharge	2	0	0	0	1	0	0	0	2	0	0	0

¹2% ophthalmic fluorescein sodium used to evaluate the absence of corneal opacity

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study dicalcium phosphate (with 3% monocalcium phosphate) was determined to be not classified in accordance with the Guidance on the application of Regulation (EC) No. 1272/2008 (EU CLP). As such no further testing is required.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin Irritation:

In order to evaluate the skin irritating potential of calcium hydrogenorthophosphate one reliable in vivo skin irritation study is available. The study performed by Bullock & Kamienski in 1972 similar to OECD 404. This skin irritation test was performed with six albino rabbits (3 per sex). A 4-hour occlusive exposure to ca. 0.5 g of the unchanged test material, produced no effects during the whole observation period on the treated sites of the animals. The mean score for the 24, 48 and 72 h reading for erythema and edema, respectively, was 0. Under the conditions of the study, the test substance is considered to be non-irritating to skin. This result is supported by a further study done in 1974. This study is not sufficient for assessment because individual scores are not given in the study report. Nevertheless, no irritating effects were observed at any time point indicating that the test substance does not have an irritating potential.

 

Eye Irritation:

Three in vivo eye irritation tests are available for calcium hydrogenorthophosphate. Two eye irritation tests were performed in 2011 and 2012. Both studies serve as key study because they were performed according to OECD Guideline 405 just with test material of different purities. The test substance used in the study done in 2012 contained 10% calcium bis (dihydrogenorthophosphate) which is classified as Eye Dam. Cat. 1. Three New Zealand White rabbits were tested with 0.1 mL of the test material, which was placed into the conjunctival sac of the right eye. After application the animals were observed for 72 hours. The study done in 2011 with 95% calcium hydrogenorthophosphate showed mean scores for the 24, 48 and 72 hour reading for cornea opacity, iritis, conjunctivae redness and chemosis were all 0.0. The study done in 2012 with 90% calcium hydrogenorthophosphate showed mean scores for the 24, 48 and 72 hour reading for cornea opacity, iritis, conjunctivae redness and chemosis were 0.0, 0.0, 0.44 and 0.0, respectively.Conjunctivae redness was fully reversible after 48 hours in 2 of the 3 animals and after 72 hours for 1 of 3 animals. Both results conclude a non-irritating potential for calcium hydrogenorthorphosphate although containg the impurity of up to 10% calcium bis(dhydrogenorthophosphate) which has eye damaging potential.

The non-irritating potential of the test material is supported by further studies done in 1974 and 1973. These studies are not sufficient for assessment because individual scores are not given in the study report. Nevertheless, no irritating effects were observed at any time point indicating that the test substance does not have an irritating potential.

 

Conclusion

Taken together, the available data on irritation/corrosion with calcium hydrogenorthophosphate (CAS 7757 -93 -9) do not indicate any hazardous potential on skin and eye. Thus, the test substance is not to be classified regarding skin and eye irritation.

Justification for classification or non-classification

The available data on skin irritation with calcium hydrogenorthophosphate do not meet the criteria for classification according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification.

The available data on eye irritation with calcium hydrogenorthophosphate do not meet the criteria for classification according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification. In addition, calcium hydrogenorthophosphate containing up to 10% calcium bis(dihydrogenorthophosphate) (classified as Eye Damage, Category 1) is also not classified in accordance with Regulation (EC) No. 1272/2008.